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1.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
2.  Abnormal daytime sleepiness in dementia with Lewy bodies compared to Alzheimer’s disease using the Multiple Sleep Latency Test 
Excessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer’s disease (AD) dementia.
A full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime Multiple Sleep Latency Test (MSLT). Neuropathologic examinations of 20 participants with DLB were carried out.
Although nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean 6.4 ± 5 minutes vs 11 ± 5 minutes, P <0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (P <0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (P <0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism or rapid eye movement sleep behavior disorder. These data suggest that abnormal daytime sleepiness is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features or sleep variables.
Daytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. Daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep–wake physiology, and further work is needed to better understand the underlying mechanisms.
PMCID: PMC4266572  PMID: 25512763
3.  Nonamnestic mild cognitive impairment progresses to dementia with Lewy bodies 
Neurology  2013;81(23):2032-2038.
To determine the rate of progression of mild cognitive impairment (MCI) to dementia with Lewy bodies (DLB).
We followed 337 patients with MCI in the Mayo Alzheimer's Disease Research Center (range 2–12 years). Competing risks survival models were used to examine the rates of progression to clinically probable DLB and Alzheimer disease (AD). A subset of patients underwent neuropathologic examination.
In this clinical cohort, 116 remained as MCI, while 49 progressed to probable DLB, 162 progressed to clinically probable AD, and 10 progressed to other dementias. Among nonamnestic MCI, progression rate to probable DLB was 20 events per 100 person-years and to probable AD was 1.6 per 100 person-years. Among amnestic MCI, progression rate to probable AD was 17 events per 100 person-years, and to DLB was 1.5 events per 100 person-years. In 88% of those who developed probable DLB, the baseline MCI diagnosis included attention and/or visuospatial deficits. Those who developed probable DLB were more likely to have baseline daytime sleepiness and subtle parkinsonism. In 99% of the clinically probable AD group, the baseline MCI diagnosis included memory impairment. Neuropathologic confirmation was obtained in 24 of 30 of those with clinically probable AD, and in 14 of 18 of those with clinically probable DLB.
In a clinical sample, patients with nonamnestic MCI were more likely to develop DLB, and those with amnestic MCI were more likely to develop probable AD.
PMCID: PMC3854825  PMID: 24212390
4.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human molecular genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson’s and Alzheimer’s diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
PMCID: PMC4222357  PMID: 24973356
5.  MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies 
Neurology  2013;81(19):1681-1689.
To determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.
Patients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.
pRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.
Presence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.
PMCID: PMC3812105  PMID: 24107861
6.  Analysis of COQ2 gene in multiple system atrophy 
Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.
We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.
The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-44) contains supplementary material, which is available to authorized users.
PMCID: PMC4233093  PMID: 25373618
COQ2; Multiple system atrophy; Genetics; CoQ10 deficiency
7.  Handedness and language learning disability differentially distribute in progressive aphasia variants 
Brain  2013;136(11):3461-3473.
Primary progressive aphasia is a neurodegenerative clinical syndrome that presents in adulthood with an isolated, progressive language disorder. Three main clinical/anatomical variants have been described, each associated with distinctive pathology. A high frequency of neurodevelopmental learning disability in primary progressive aphasia has been reported. Because the disorder is heterogeneous with different patterns of cognitive, anatomical and biological involvement, we sought to identify whether learning disability had a predilection for one or more of the primary progressive aphasia subtypes. We screened the University of California San Francisco Memory and Aging Center's primary progressive aphasia cohort (n = 198) for history of language-related learning disability as well as hand preference, which has associations with learning disability. The study included logopenic (n = 48), non-fluent (n = 54) and semantic (n = 96) variant primary progressive aphasias. We investigated whether the presence of learning disability or non-right-handedness was associated with differential effects on demographic, neuropsychological and neuroimaging features of primary progressive aphasia. We showed that a high frequency of learning disability was present only in the logopenic group (χ2 = 15.17, P < 0.001) and (χ2 = 11.51, P < 0.001) compared with semantic and non-fluent populations. In this group, learning disability was associated with earlier onset of disease, more isolated language symptoms, and more focal pattern of left posterior temporoparietal atrophy. Non-right-handedness was instead over-represented in the semantic group, at nearly twice the prevalence of the general population (χ2 = 6.34, P = 0.01). Within semantic variant primary progressive aphasia the right-handed and non-right-handed cohorts appeared homogeneous on imaging, cognitive profile, and structural analysis of brain symmetry. Lastly, the non-fluent group showed no increase in learning disability or non-right-handedness. Logopenic variant primary progressive aphasia and developmental dyslexia both manifest with phonological disturbances and posterior temporal involvement. Learning disability might confer vulnerability of this network to early-onset, focal Alzheimer’s pathology. Left-handedness has been described as a proxy for atypical brain hemispheric lateralization. As non-right-handedness was increased only in the semantic group, anomalous lateralization mechanisms might instead be related to frontotemporal lobar degeneration with abnormal TARDBP. Taken together, this study suggests that neurodevelopmental signatures impart differential trajectories towards neurodegenerative disease.
PMCID: PMC3808687  PMID: 24056533
Alzheimer’s disease; frontotemporal dementia; dementia aphasia; case control study; risk factors in epidemiology
8.  A nonsense mutation in PRNP associated with clinical Alzheimer's disease☆ 
Neurobiology of Aging  2014;35(11):2656.e13-2656.e16.
Here, we describe a nonsense haplotype in PRNP associated with clinical Alzheimer's disease. The patient presented an early-onset of cognitive decline with memory loss as the primary cognitive problem. Whole-exome sequencing revealed a nonsense mutation in PRNP (NM_000311, c.C478T; p.Q160*; rs80356711) associated with homozygosity for the V allele at position 129 of the protein, further highlighting how very similar genotypes in PRNP result in strikingly different phenotypes.
PMCID: PMC4175176  PMID: 24958194
Alzheimer's disease; Prion; PRNP; Nonsense mutation; Exome sequencing
9.  A nonsense mutation in PRNP associated with clinical Alzheimer’s disease 
Neurobiology of aging  2014;35(11):2656.e13-2656.e16.
Here, we describe a nonsense haplotype in PRNP associated with clinical Alzheimer’s disease. The patient presented an early-onset of cognitive decline with memory loss as the primary cognitive problem. Whole-exome sequencing revealed a nonsense mutation in PRNP (NM_000311, c.C478T; p.Q160*; rs80356711) associated with homozygosity for the V allele at position 129 of the protein, further highlighting how very similar genotypes in PRNP result in strikingly different phenotypes.
PMCID: PMC4175176  PMID: 24958194
Alzheimer’s disease; Prion; PRNP; Nonsense mutation; Exome sequencing
10.  Associations of repeat sizes with clinical and pathological characteristics in C9ORF72 expansion carriers (Xpansize-72): a cross-sectional cohort study 
Lancet neurology  2013;12(10):10.1016/S1474-4422(13)70210-2.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are currently the major genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). Presently, it is unknown whether expansion size affects disease severity or phenotypes.
We performed a cross-sectional Southern blot characterization study (Xpansize-72) in a cohort of subjects obtained at the Mayo Clinic and Banner Sun Health Research Institute. All subjects carried GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from the frontal cortex, cerebellum and/or blood. Southern blotting techniques and densitometry were employed to estimate the repeat size of the most abundant expansion species. Comparisons of repeat sizes between tissues were made using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. The association of repeat size with age at onset and age at collection was evaluated using a Spearman’s test of correlation; whereas the association between repeat size and survival after disease onset was examined using Cox proportional hazards regression models.
Our cohort consisted of 84 C9ORF72 expansion carriers, including FTD patients (n=35), FTD/MND patients (n=16), MND patients (n=30), and unaffected subjects (n=3). We focused our analysis on three major tissue subgroups: frontal cortex (41 subjects [21 FTD, 11 FTD/MND, 9 MND]), cerebellum (40 subjects [20 FTD, 12 FTD/MND, 8 MND]), and blood (50 subjects [15 FTD, 9 FTD/MND, 23 MND, 3 unaffected expansion carriers]). Repeat lengths in the cerebellum were significantly smaller (median 12·3 kb [~1667 repeat units], IQR 11·1–14·3) than in the frontal cortex (median 33·8 kb [~5250 repeat units], IQR 23·5–44·9, p<0·0001), or in blood (median 18·6 kb [~2717 repeat units], IQR 13·9–28·1, p=0·0002). Within these tissues, there was no significant difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of FTD patients, repeat length correlated with age at onset (r=0·63, p=0·003) and age at collection (r=0·58, p=0·006); this correlation was not detected in the cerebellum or blood. Finally, only in the cerebellum, survival after disease onset was poorer in patients from our overall cohort with repeat lengths greater than 1467 repeat units (25th percentile, HR 3·27, 95% CI 1·34–7·95, p=0·009): the median survival was 4·8 years (IQR 3·0–7·4) in the group with longer expansions versus 7·4 years (IQR 6·3–10·9) in the group with smaller expansions.
Substantial variation in repeat size is observed between cerebellum, frontal cortex, and blood; relatively long repeat sizes in the cerebellum confer an important survival disadvantage. Our findings indicate that expansion size does affect disease severity, which could be relevant for genetic counseling.
PMCID: PMC3879782  PMID: 24011653
11.  Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene 
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.
PMCID: PMC4190282  PMID: 25239657
C9ORF72; Frontotemporal dementia; Motor neuron disease; Genetic modifier; Repeat expansion
12.  Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies 
Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer’s disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
PMCID: PMC4162987  PMID: 25217249
Alzheimer’s disease; Genetic; Heterogeneity; Presenilin; Amyloid precursor protein; Apolipoprotein E
13.  Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia 
Mutations in profilin-1 (PFN1) have recently been identified in patients with amyotrophic lateral sclerosis (ALS). Because of the considerable overlap between ALS and the common subtype of frontotemporal dementia, which is characterized by transactive response DNA-binding protein 43 pathology (FTLD-TDP), we tested cohorts of ALS and FTLD-TDP patients for PFN1 mutations.
DNA was obtained from 342 ALS patients and 141 FTLD-TDP patients at our outpatient clinic and brain bank for neurodegenerative diseases at the Mayo Clinic Florida, Jacksonville, USA. We screened these patients for mutations in coding regions of PFN1 by Sanger sequencing. Subsequently, we used TaqMan genotyping assays to investigate the identified variant in 1167 control subjects.
One variant, p.E117G, was detected in 1 ALS patient, 1 FTLD-TDP patient, and 2 control subjects. The mutation frequency of patients versus control subjects was not significantly different (p-value = 0.36). Moreover, PFN1 and TDP-43 staining of autopsy material did not differ between patients with or without this variant.
The p.E117G variant appears to represent a benign polymorphism. PFN1 mutations, in general, are rare in ALS and FTLD-TDP patients.
PMCID: PMC3923463  PMID: 23634771
Amyotrophic lateral sclerosis; frontotemporal dementia; profilin-1; TDP-43; genetics
14.  TDP-43 Frontotemporal Lobar Degeneration and Autoimmune Disease 
Journal of neurology, neurosurgery, and psychiatry  2013;84(9):10.1136/jnnp-2012-304644.
The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored.
To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls.
Case control.
Academic medical centres.
129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels.
Outcome Measures
Chi-square comparison of autoimmune prevalence and follow up logistic regression.
There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC.
svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.
PMCID: PMC3840954  PMID: 23543794
15.  TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia 
Journal of neurochemistry  2013;126(6):781-791.
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLDTDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and TMEM106B protein regulation.
First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of PGRN levels showed similar effects upon T185 and S185 TMEM106B overexpression. However, overexpression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk.
PMCID: PMC3766501  PMID: 23742080
TMEM106B; frontotemporal dementia; progranulin; glycosylation
16.  Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels 
MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this.
We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer’s Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated.
H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03).
These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression.
PMCID: PMC4198935  PMID: 25324900
17.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human Molecular Genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
PMCID: PMC4222357  PMID: 24973356
18.  Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis 
Neurology  2013;80(19):1771-1777.
We examined the clinical and pathologic phenotypes of GRN mutation carriers with the pathogenic A9D (g.26C>A) missense mutation.
Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination.
The clinical diagnoses of patients with GRN A9D mutations were amyotrophic lateral sclerosis, atypical extrapyramidal disorder, and behavioral variant frontotemporal dementia. Immunohistochemistry for TAR DNA-binding protein 43 (TDP-43) revealed variability in morphology and distribution of pathology. One patient had notable involvement of motor neurons in the spinal cord as well as type B TDP-43, whereas 2 other patients had type A TDP-43.
The clinical presentation of the GRN A9D missense mutation is not restricted to behavioral variant frontotemporal dementia and may include aphasia, extrapyramidal features, and, notably, amyotrophic lateral sclerosis.
PMCID: PMC3719429  PMID: 23596077
19.  Age-Specific Incidence Rates for Dementia and Alzheimer Disease in NIA-LOAD/NCRAD and EFIGA Families 
JAMA neurology  2014;71(3):315-323.
Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD.
To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies.
Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study.
Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD.
The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71).
The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease–related genes in these families or shared environmental risks.
PMCID: PMC4000602  PMID: 24425039
20.  C9ORF72 repeat expansions in cases with previously identified pathogenic mutations 
Neurology  2013;81(15):1332-1341.
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.
A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.
We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.
Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
PMCID: PMC3806926  PMID: 24027057
21.  CSF1R mutations link POLD and HDLS as a single disease entity 
Neurology  2013;80(11):1033-1040.
Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD.
We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed.
We identified CSF1R mutations in both POLD families: in family 5901, we found c.2297T>C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G>A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wild-type CSF1R.
We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity.
PMCID: PMC3653204  PMID: 23408870
22.  ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease 
Recent genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these “actionable” variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D’ = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5×10−05; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D’ = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
PMCID: PMC3995879  PMID: 24607147
23.  TARDBP mutations in Parkinson’s disease 
Parkinsonism & related disorders  2012;19(3):312-315.
Mutations of the TARDBP gene encoding TDP-43 protein have been shown to cause amyotrophic lateral sclerosis and have been reported to present with clinical heterogeneity including parkinsonism. In addition, TDP-43 pathology has been observed across a spectrum of neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Herein we report the presence of a TDP-43 mutation in a patient with a clinical diagnosis of Parkinson’s disease. The TDP-43 p.N267S substitution has been previously implicated in both amyotrophic lateral sclerosis and behavioral variant frontotemporal dementia. Our findings widen the phenotypic presentation for the TDP-43 p.N267S substitution and support a possible role for rare TDP-43 mutations presenting with Parkinson’s disease.
PMCID: PMC3582838  PMID: 23231971
TDP-43; amyotrophic lateral sclerosis; Parkinson’s disease
24.  Analysis of the C9orf72 repeat in Parkinson’s disease, essential tremor and restless legs syndrome 
Parkinsonism & related disorders  2012;19(2):198-201.
The hexanucleotide expanded repeat (GGGGCC) in intron 1 of the C9orf72 gene is recognized as the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, as part of the clinical phenotype, some patients present with parkinsonism. The present study investigated the potential expansion or association of the C9orf72 repeat length with susceptibility to Parkinson’s disease and related disorders, essential tremor and restless legs syndrome. One restless legs syndrome patient was shown to harbor a repeat expansion, however on clinical follow-up this patient was observed to have developed frontotemporal dementia. There was no evidence of association of repeat length on disease risk or age-at-onset for any of the three disorders. Therefore the C9orf72 hexanucleotide repeat expansion appears to be specific to TDP-43 driven amyotrophic lateral sclerosis and dementia.
PMCID: PMC3570692  PMID: 23084342
C9orf72; expanded repeat; PD; ET; RLS; genetic association
25.  Corticospinal tract degeneration associated with TDP-43 type C pathology and semantic dementia 
Brain  2013;136(2):455-470.
Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A–D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.
PMCID: PMC3572926  PMID: 23358603
TDP-43 type C; corticospinal tract; MRI; semantic dementia; right temporal lobe

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